Summary of Work: A variety of man-made particles are sources of environmental fibroproliferative lung diseases. A key feature of these diseases is fibroblast hyperplasia. We postulate that the platelet-derived growth factor (PDGF) receptor system is pivotal to the progression of these diseases. Fibrogenic particles cause lung injury and stimulate macrophages to produce inflammatory mediators that modulate PDGF receptor expression (e.g., interleukin-1b (IL-1b), transforming growth factor b1 (TGF-b1) and prostaglandin-E2 (PGE2). We have shown that IL-1b upregulates the PDGF alpha receptor and increases the mitogenic and chemotactic responses of lung fibroblasts to PDGF. In contrast, TGF-b1 and PGE2 down-regulate the PDGF receptor system and suppress fibroblast growth. The particle-associated agents that mediate the inflammatory responses and subsequent PDGF receptor alteration are endotoxin and metals. Induction of PDGF alpha receptors occurs in vivo following metal induced lung injury in rats and precedes fibroblast hyperplasia. IL-1b-induced expression of the PDGF alpha receptor in vitro is dependent on p38 MAP kinase, but not the ERK MAP kinases or JNK MAP kinase. Our most recent studies, which have investigated nuclear localization of NFkB (p50/p65 proteins) by gel shift/supershift and the coordinated degradation of IkB-alpha, suggest that IL-1b does not appear to induce the PDGF receptor through a classic NFkB pathway. Future work will focus on: 1) elucidation of transcription factor(s) which mediate PDGF receptor up-regulation and 2) overexpression of a soluble extracellular PDGF receptor to inhibit the progression of lung fibrosis in rats and mice. It is anticipated that this research will lead to strategies for the intervention pulmonary fibroproliferative lung fibrosisdisease.